Ataluren (formerly known as PTC124), which is chemically named as 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid, is an orally administered small-molecule compound for the treatment of patients with genetic disorders (e.g., Duchenne muscular dystrophy (DMD) and cystic fibrosis) caused due to a nonsense mutation. Ataluren is discovered and designed by PTC Therapeutics, Inc. and is sold under the trade name Translarna™ in the European Union. Translarna™ is the first treatment approved for the underlying cause of DMD. The European Medicines Agency (EMA) has designated ataluren as an orphan medicinal product.
Publications related to ataluren reveal several synthetic approaches which have mostly been disclosed by PTC Therapeutics, Inc. The synthetic approaches disclosed in the prior art are described below.
WO 2006/110483 A1 discloses methods for preparing ataluren. As specifically illustrated in FIG. 1, 3-cyanobenzoic acid methyl ester compound 1 was reacted with hydroxylamine to form oxime compound 2 as white powder. The oxime compound 2 was contacted with 2-fluorobenzoyl chloride to form compound 3 under basic condition. Then put compound 3 into toluene at high temperature to complete condensation and form oxadiazole compound 4. The compound 4 was subjected to hydrolysis conditions (aqueous NaOH) and then ataluren formed as white powder. The overall yield from compound 1 to ataluren was about 73%.
Another approach is a one-pot process disclosed in U.S. Pat. Nos. 7,678,922 B2 and 8,367,841 B2 (see FIG. 2). The synthetic route also started from 3-cyanobenzoic acid methyl ester compound 1 without the isolation of compounds 2, 3 and 4 to afford ataluren. Tert-Butanol was used as the main solvent system through this route, even in the final hydrolysis step. The overall yield from compound 1 to ataluren was about 67-69%.
Still another one-pot process of ataluren disclosed in U.S. Pat. Nos. 7,678,922 B2 and 8,367,841 B2 is started from 3-cyanobenzoic acid, compound 5, without the isolation of compounds 6 and 7 (see FIG. 3). Tert-Butanol was also used as the main solvent system for this approach. The overall isolation yield of ataluren was about 76%.
Although numerous approaches for preparing ataluren have been disclosed as discussed above, there is still an unmet need for a mild, cleaner and easier process for industrial preparation of ataluren. The present processes disclosed herein address this need and other needs.